Each kidney is composed of around one million nephrons. The glomerulus, a component of the nephron, is comprised of a bundle of parallel capillaries, this structure being referred to as the Bowman's capsule the function of the glomerulus is to filter water and solutes from the blood.
Glomerulonephritis is a disease of the kidney which is characterised by the inflammation of the glomeruli. Inflammation of the glomerulus compromises glomerular function, this resulting in a narrowing or blocking of the capillaries which results in a disruption to normal glomerular filtration.
Glomrulonephritis can result in large amounts of protein being passed into the urine, in a condition known as proteinuria. Further symptoms of glomerulonephritis may include excessive blood urea nitrogen (uremia), haematuria, hyperlipidemia, a reduction in glomerular filtration rate, hypoalbuminaemia and lipiduria.
Current treatments for glomerulonephritis include the administration of corticosteroids and/or non-steroidal anti-inflammatory drugs. In more severe cases, blood dialysis or organ transplantation may be required. Such therapies are however unsatisfactory for a number of reasons. In the case of corticosteroid use, this being the most commonly employed therapy for the treatment of glomerulonephritis, the treatment has to be managed carefully in order to limit the immune suppression of the patient which can result from prolonged steroid administration. Further, the burden or long term dialysis, or the risks associated with transplant surgery and organ rejection also make these therapies less desirable.
Accordingly, there is a pressing need for a therapeutic treatment which can be targeted to the inflamed glomerulus in order to prevent or treat the inflamed glomerulus during glomerulonephritis and which does not suffer from the disadvantages and side effects of the hitherto known treatments.
Toll-like Receptors (TLRs) form a family of pattern recognition receptors which have a key role in activating the innate immune response. 11 Toll-like Receptors have been identified in humans to date. The members of the Toll-like Receptor family are highly conserved, with most mammalian species having between 10 to 15 Toll-like Receptors. Each Toll-like Receptor recognises specific pathogen-associated molecular signatures. For example, Toll-like Receptor 2 (TLR2, CD282, TLR-2) can be activated by peptidoglycan, lipoproteins and lipoteichoic acid. Toll-like Receptors are known to form either homodimers or heterodimers wherein each dimer has a different ligand specificity. TLR2 forms a heterodimer with either TLR1 or TLR6 and possibly also TLR10, in some instances, to form a membrane bound receptor complex. In addition, the ectodomain of Toll-like Receptor 2 is known to form a soluble heterodimer with the CD14 protein in the circulatory system and also in mammalian milk.
Ligand binding to Toll-like Receptor 2 results in downstream signalling involving cytoplasmic adaptor proteins such as MyD88 and Mal (MyD88-adaptor like), which is also known as TIRAP (Toll-Interleukin-1 receptor domain containing adaptor protein).
The involvement of Toll-like Receptor 2 and Toll-like Receptor 2-induced signalling and immune system activation has implicated Toll-like Receptor 2 as an important mediator in the development of inflammation and immune-mediated disease. Accordingly there has been significant therapeutic interest in relation to the modulation of the Toll-like Receptor 2 signalling pathway. Toll-like Receptor 2 mediated intracellular signaling results in activation of the innate immune system. However, in some instances, the activation of the innate immune system which results following Toll-like Receptor 2 activation has been shown to be a factor in causing inflammation and immune-mediated disease. As such, a number of therapeutic approaches have sought to block TLR-2 ligand binding, or which suppress the functional activity of Toll-like Receptor 2 following ligand binding, for example by suppressing Toll-like Receptor 2 mediated intracellular signalling which results following Toll-like Receptor 2 activation.
In relation to the pathology of kidney disease, Toll-like Receptor 2 has been shown to be involved in the induction of the antigen-specific adaptive immune response associated with the development and recurrence of immune-mediated kidney disease such as glomerulonephritis. Specifically, it has been shown that a Toll-like Receptor 2 ligand, lipopeptide, can exacerbate nephrotoxic nephritis in a Toll-like Receptor 2-dependent manner. Toll-like Receptor 2 activation showed an increased amount of antigen specific IgG isotypes such as IgG1, IgG2b, IgG3 in the serum and IgG2b and IgG3 are seen to be deposited within the glomerulus. Elevated CD4+ positive T cell infiltration was also observed in the glomerulus. Nevertheless, there has been no evidence to date to suggest that blocking the Toll-like Receptor 2 pathway would provide a basis for a treatment for immune-mediated kidney disorders.
Following extensive experimentation, the inventors have surprisingly identified that compounds which antagonise Toll-like Receptor 2 function, for example by blocking Toll-like Receptor 2 ligand binding, or by blocking intracellular signalling mediated by activated Toll-like Receptor 2, cause a reduction in the level of inflammation in the kidney. The inventors have identified that such compounds have utility in methods for the treatment of inflammatory conditions of the kidney, and in particular for the treatment of conditions such as glomerulonephritis. In particular, the inventors have surprisingly shown that blocking Toll-like Receptor 2 ligand binding, through the use of an antibody, or a functional binding fragment thereof, which has binding specificity to at least one binding epitopes present on Toll-like Receptor 2, and which inhibits ligand binding to Toll-like Receptor 2, can suppress the production of neutrophils, and suppress albuminuria and thrombosis which are typically elevated during onset of glomerulonephritis. As such, compounds which mediate such an effect downregulate Toll-like Receptor 2 mediated activation and downstream TLR-2 induced intracellular signalling.